The molecular basis for the actions of three classes of hallucinogens will be determined: lysergic acid derivatives e.g., LSD; phenylalkylamines e.g., mescaline and 2,5-dimethyl-4-methylamphetamine; and indolealkylamines e.g., psilocin. The high-affinity binding sites (receptors) for these substances will be characterized in different parts of the brain and in the fundus portion of the stomach which has a very similar receptor. The actions of the hallucinogenci substances on the formation of cyclic-AMP and cyclic-GMP will be measured including their influence on cyclases sensitive to putative neurotransmitters. The relationship of the receptors and of the cyclases to each other and to serotonergic, adrenergic, dopaminergic and tryptaminergic mechanism at presynaptic and postsynaptic sites will be examined. Quantum mechanical studies (ab-initio and non-empirical) of the electronic structure and reactivity characteristics of the hallucinogens and related compounds, including the putative neurotransmitters, will be used to learn the basis of their high-affinity binding and their action on cyclases. The physicochemical properties of the drugs will be revealed by the calculations and by spectroscopic measurements including nuclear magnetic resonance. Membranes containing the receptors and the cyclases will be altered by enzymes and chemicals in order to gain insight into the structural requirements for these activities. Attempts will be made to enrich the particulate material containing the receptors and the cyclases; and to solubilize and purify the receptors. Physicochemical and quantum chemical methods will be used to analyze the interaction between the hallucinogens and the solubilized receptor or the enriched particulate material containing the receptors. These results will reveal the molecular basis for the interactions including the groupings involved in the interaction; the forces involved in the interaction; the geometry of the complex; and the biological consequences of the interaction. This understanding will be used to design prototypic molecules to interact with the receptors and thereby influence the action of the hallucinogenic drugs.